Several epidemiological studies have shown that women, compared to men, are at a substantially greater risk of depression beginning in adolescence and continuing through their entire life. In addition, the age-specific incidence of depression in women peaks during the late reproductive years. However, the extent to which the perimenopause represents a time of greater risk for new onset of depression in women with no history of mood disorder is yet to be determined. The Harvard Study of Moods and Cycles (HSMC), a population-based prospective study of late premenopausal aged women, is uniquely suited to investigate this association because of the rigorous systematic assessment of psychiatric morbidity and menstrual cycle changes over time. In this study, approximately 1000 premenopausal women with and without a lifetime history of depression were followed over 36 months with semi-annual psychiatric assessments, medical history interviews, and early follicular phase blood specimens to measure reproductive hormones in serum. Our published results have shown that 1) age at menarche and other events in early reproductive life are associated with risk for depression, 2) women with a lifetime history of major depression (particularly those with more severe depressive symptoms proximate to the perimenopause) are at a greater risk of developing menstrual cycle changes consistent with those that signal an earlier transition to the perimenopause compared to women with no depression history, and 3) early follicular phase FSH and LH are higher, and estradiol levels are lower in depressed compared to non-depressed late reproductive aged women as they move toward the climacteric. Having carefully gathered prospective data on psychiatric disorders and changes in menstruation, we now have a unique opportunity to evaluate the impact of the perimenopausal transition on risk of first onset of mood disturbance. In this current submission, we plan to include approximately 500 women from the original HSMC with no lifetime history of major depression, and will enrich this sample with an additional 200 largely minority women from the general population. Our preliminary data suggest that an earlier onset to the perimenopausal transition is associated with a 3-fold risk of new onset of major depression in women with no prior history of depressive disorder. Furthermore, it appears that initiation of hormonal therapy to treat menstrual cycle changes, irregularities, or somatic symptoms attenuates this increased risk of a first onset of depressive episode. We plan to better assess the effect of onset to the perimenopause on the risk for new onset of mood disturbance independent of past depression history that clearly influences the risk of recurrent episodes. The present project is designed to confirm and expand upon these preliminary findings by using structured clinical interviews for accurate psychiatric diagnoses, and comprehensive assessments of clinical symptoms at the time of the menopausal transition.